This invention relates to improved capsule compositions and structures of pharmaceutical compounds which are difficult to administer orally and more specifically relates to oral unitary dosage forms of therapeutic materials which are subject to degradation under gastric conditions, such as digestive enzymes, and especially pancreatic preparations of animal origin.
Digestive enzyme replacement therapy is beneficial in patients with cystic fibrosis, chronic pancreatitis, post-pancreatectomy, ductal obstructions caused by tumors of the pancreas, pancreatic insufficiency, steatorrhea of malabsorption syndrome and post-gastrectomy (Bilroth II and total) and for betagalactosidase deficiency. Many products are currently marketed for enzyme replacement therapy where pancreatic exocrine insuffiency exists. Various types of enteric-coated tablets, capsules, enzyme powders and mixtures of enzymes with anticholinergics and barbituates are included among the products which are now sold. While it is difficult to assess efficiency of the various protective means that have been employed, the large number of combinations of coatings, buffers, antiacids, H.sub.2 receptor antagonists and so on, coupled with the literature's conflicting views as to their effectiveness leads to the conclusion that optimal dosage forms or regimens have not yet been developed.
Pancreatic enzymes are active under neutral or slightly alkaline conditions. In the presence of acid pH and pepsin, that is under the conditions encountered in the mammalian stomach, they are irreversibly inactivated and totally lose their biological activity. It it recognized by the art that orally administered pancreatic enzymes must be protected from degradation during passage through the stomach. While various enteric coatings have been reported in the prior art, they are hampered by several problems and have thus not been accepted without reservation because most of them are permeable to gastric fluids or they fail to disintegrate promptly upon passage into the duodenum to allow rapid mixing with the chyme so as to achieve maximum biological effect.
In the normal physiological state, the stomach contents encounter pepsin which is activated by hydrochloric acid. Both the enzymatic action of pepsin and the strong acid pH of the stomach (pH 1.2 to 1.8) destroy the activity of these enzymes. There are several problems encountered with the use of entericcoated capsules which are dependent upon pH levels for release of their activity. In a study by Regan et al, New England Journal of Medicine 297, No. 16:854-858, 1977, it was found that an enteric coated capsule released approximately 50% of the total enzyme activity in thirty minutes when incubated at pH 6 to 7. Another problem with enteric coatings of this type is that in patients with persistent steatorrhea, intragastric pH was higher during the initial forty minutes. Enzyme was probably released by the enteric coating only to be later inactivated as the pH fell below 4.
The presence of food in the gastro-intestinal tract causes the release of secretagogues that stimulate the flow of enzymes and bicarbonate by the pancreas. Enzymes of the pancreas are secreted in the form of inactivated zymogens. Upon entry into the duodenum, enterokinase converts trypsinogen which is inactive into the active form called trypsin. Trypsin catalyzes the conversion of all enzyme precursors into their active forms. The acidic mixture from the stomach is neutralized by the bicarbonate secretion of the normal pancreas. Trypsin activity is reduced to less than 10% fo its original value in fifteen minutes by incubation with pepsin at pH 1.6. Since pancreatic exocrine insufficiency often has inadequate bicarbonate secretion as a component of the disease, it is wrong to assume that reliable release of pH activated enteric coatings can work in all situations. While oral dosing is the most practical means for chronically controlling several disease states, it requires the use of gross amounts of digestive enzymes far in excess of those endogenously needed in order to compensate for gastric inactivation and to achieve delivery with effective biological activity levels into the intestinal tract.